Everything You Need to Know About HCG * (*and were frightened to ask)

1. Everything You Need to Know About HCG * (*and were frightened to ask) • Lab Rounds - June 5, 2003 • Robbie N Drummond

2. Nine Questions about HCG • What is HCG? • How Many days after conception does HCG appear in the urine? • What is the doubling time of serum HCG when followed serially? • At What level of serum HCG can a gestational sac be seen with U/S? • Transabdominal U/S vs Transvaginal U/S • What happens to HCG if a miscarriage is underway? • What happens to HCG if an ectopic pregnancy is present? • What is a heterotropic pregnancy? • How can HCG be used to guide the nonsurgical ablation of an ectopic pregnancy? • What other condition is characterized by a progressive increase in HCG?

3. What is HCG?

4. a complex glycoprotein produced exclusively by syncytio trophoblast • detectable shortly after implantation into the uterine wall • negative feedback to the pituitary gland and hypothalamus to prevent menstruation • Alpha and beta subunit • Alpha almost identical in TSH, FSH, and LH • B subunit specific for HCG • Placenta only normal tissue that secretes HCG in premenopausal women

5. Excellent marker for the well being of the pregnancy • Extremely sensitive test .....if a patient is pregnant HCG is present • Also a very specific test but needs to be qualified by type of pregnancy • Ie., ectopic vs intrauterine vs miscarrying vs trophoblastic

6. Detected by a radio immuno assay • highly specific antiserum to HCG • sensitivity between 25 and 50 IU/L. • Can detect levels as low as 2 to 7 mIU • Results less than 5 considered to be negative

7. How Many days after conception does HCG appear in the urine?

8. Standard urine test is 99% sensitive and 99% specific • 7 days after ovulation, the implanted trophoblast begins to secrete hCG • 100 mIU/mL in maternal serum by the expected date of the missed menses

9. based on the detection of the beta subunit core. • Standard tests used sensitivity 5 to 25 mIU/mL of B-hCG. • home pregnancy tests lower sensitivity and specificity

10. considered "qualitative" for pregnancy, • can either rule pregnancy in or out but cannot reliably predict the level of hCG • Caveat: urine specific gravity greater than 1.010 (first morning catch) • False negative can occur with gross hematuria protein greater than 2+ or dilute urine • New research on quantitative urine pregnancy testing

11. What is the doubling time of serum HCG when followed serially?

12. early in pregnancy HCG rise is linear • doubling time 48 hours viable pregnancy • 85% rise by at least 66 % every 48 hours • during first 40 days of pregnancy • conversely only 15 % increase less than 66 % • 50% or less in a 48 hour period = non viable pregnancy • doubling time falls off after 41 and then 65 days

14. <5 weeks: no gestational sac on tv u/s, <1800 HCG • 5 week: gestational sac 1800 HCG • 5.5week: yolk sac 1800 –3500 HCG • 6wk: embryonic pole >3500 HCG • >6 weeks: cardiac activity 3500 HCG

15. At What level of serum HCG can a gestational sac be seen with U/S? • Transabdominal U/S vs Transvaginal U/S

16. Intrauterine pregnancy visible once hcg 6000 –6500 on transabdominal U/S • IUP clearly seen by transvaginal U/S at 2000 • ie 1 week earlier

17. although above 1000 most IUP’s seen on u/s • generally accepted value at 1500 • Discriminatory zone 1000 to 1500 • If > 1500 EP suspected if TV u/s no gestational sac • If ,1500 and multiple sign and sx’s or hemodynamically unstable intervene

18. november 1998 Fertility Mol et al • 354 consecutive pts prospective study • advise caution discriminatory zone1000 – 2000 • 1500 with fluid in cul de sac or ectopic mass dx’c • cut off at 2000 without these findings

19. What happens to HCG do if a miscarriage is underway?

20. In miscarriage and ectopic pregnancy • death of the trophoblast, a decline in betahCG,. • plateaued or stable over 48 hours, or if it should fall, • pregnancy is almost certainly doomed. • The half-life of betahCG in the serum is about 1 to 3 days. • May still be present even weeks later • If all placenta is removed by treatment, the betahCG should fall steadily.[

21. Failure to decline = live placental tissue • retained products after a d&c • retained live placenta in the site of an ectopic pregnancy that had been treated conservatively • Can do diagnositic d&c if uterus empty look for chorionic villi confirms miscarriage

22. What happens to HCG if an ectopic pregnancy is present?

23. Between 40 and 50 percent of ectopic pregnancies are misdiagnosed at the initial visit • EP in 1992 9.7 cases per 1000 (4.5 in 1970) • Increase in certain risk factors but increase early dx EP • Same timeframe: Case fatality dropped from 36 per 10000 to 3.8

24. 68 to 77 % of ectopic pregnancies resolve without intervention • no marker identifies which subset will be a self limited disease • expectant management an option with close f/u • ectopic pregnancy must be less than 3.5 cm in diameter with declining bHCG levels

25. What is a heterotropic pregnancy?

26. one in 2,600 pregnancies • co-existence of intrauterine and ectopic pregnancy • With fertility treatments, the incidence of heterotopic pregnancy increases to as high as 3 percent • Heterotopic pregnancy is extremely difficult to diagnose, and 50 percent of cases are identified only after tubal rupture • Methotrexate treats both • In this case, the finding of placenta on D&C does not rule out ectopic pregnancy, and further treatment is urgently needed

27. How can HCG be used to guide the nonsurgical ablation of an ectopic pregnancy

28. most recent development use of single dose methotrexate • direct injection or systemic use • 11 studies since1991 with success rates75 –96 % • single doses have replaced multiple doses • single dose protocol 50 mg per sq meter of body surface area • serum hcg measured of days 1, 4 , and 7 • levels often rise till day 4 • if declines less then 15% day 4 and 7 protocol repeated • hcg measured weekly if greater 15% till less than 15 mIU

29. Lipscomb et al have shown a clear correlation between success and low beta HCG levels: • <1000 98 % • 1000- 1999 93% • 2000 – 4999 91.8 % • 5000 – 9999 86.7% • 10000 – 14999 81.8 %

30. 20% of women require more than one treatment • time to resolution 35 days • may take 109 days • not effective if HCG greater than 5000 • complications pain, hematomas, methotrexate toxicity

31. What other condition is characterized by a progressive increase in HCG?

32. The incidence of trophoblasticdisease in the United States is in 1 in 1000 - 1500 pregnancies. • much more common in certain other parts of the world, particularly Southeast Asia • (1) pregnancy at the extremes of reproductive age (particularly advanced age over 45) and • (2) previous molar disease

33. hydatidiform molar pregnancy, • invasive molar pregnancy, • choriocarcinoma, • placental-site trophoblastic tumor. • A unique feature of gestational trophoblastic tumors is their ability to be cured, even in the setting of disseminated metastatic disease, because these tumors are sensitive to several chemotherapeutic agents.[1]

34. M olar pregnancies associated with higher than expected hcg >100,000 • High hCG levels in association with a known diagnosis of gestational trophoblastic tumor is reflective of total tumor burden and correlates with a greater chance of treatment failure • HCG tumour marker to follow course of treatment and stage of disease

37. TAKE HOME POINTS • HCG highly sensitive and specific for pregnancy • Urine qualitative test Serum quantitative • Hcg doubles in serum every 48 hours during first two months of gestation • Below 1500 U/S not useful in determining site of pregnancy • HCG levels guide non surgical treatment of Ectopic Pregnancy • Remember trophoblastic disease with high HCG levels